Arima syndrome caused by CEP290 specific variant and accompanied with pathological cilium; clinical comparison with Joubert syndrome and its related diseases

Objective

Arima syndrome (AS) is a rare disease and its clinical features mimic those of Joubert syndrome or Joubert syndrome-related diseases (JSRD). Recently, we clarified the AS diagnostic criteria and its severe phenotype. However, genetic evidence of AS remains unknown. We explored causative genes of AS and compared the clinical and genetic features of AS with the other JSRD.

Interstitial deletion of 13q14.13-q32.3 presenting with Arima syndrome and bilateral retinoblastoma

A patient with a large deletion of the distal part of the long arm of chromosome 13 showed severe psychomotor retardation, a characteristic face, nystagmus, retinopathy, cystic kidney disease, and brain malformation with molar tooth sign and cerebellar vermis hypoplasia, a phenotype typical of Arima syndrome. This patient also had bilateral retinoblastoma. Fluorescent in situ hybridization and single-nucleotide-polymorphism genotyping microarray demonstrated an interstitial deletion of 54 Mbp, ranging from 13q14.13 to 13q32.3 and involving the RB1 gene. This patient is the first case of Arima syndrome, or a Joubert syndrome-related disorder, that showed linkage to chromosome 13q.     

Nationwide survey of childhood Guillain-Barré syndrome,Fisher syndrome,and Bickerstaff brainstem encephalitis in Japan

ObjectiveGuillain-Barré syndrome (GBS), Fisher syndrome (FS), and Bickerstaff brainstem encephalitis (BBE) are immune-mediated neuropathies presenting with symptoms such as weakness, ophthalmoplegia, ataxia, and consciousness disturbances. Although the epidemiology of GBS and BBE in patients of all ages has been reported, childhood data have not been well-investigated. We aimed to determine the clinical features, therapeutics, and prognoses of childhood GBS, FS, and BBE in Japan.MethodsWe sent questionnaires to 1068 pediatric neurologists in Japan from 2014 to 2016 to determine the number of children less than 15 years old with GBS, FS, or BBE and their age and sex. We subsequently performed a secondary survey to investigate the clinical features, laboratory data, treatment, and prognosis.ResultsFive-hundred thirty-eight pediatric neurology specialists (50.4%) responded to the first survey. The total number of children with GBS, FS, and BBE in Japan from 2014 to 2016 were 87, 10, and 6, respectively. GBS was classified as acute inflammatory demyelinating neuropathy (35.6%), acute motor axonal neuropathy (20.7%), or acute motor-sensory axonal neuropathy (10.3%), with a male-to-female ratio of 1.29:1.0 and a wide distribution of onset ages. The disease severities of GBS, FS, and BBE were variable, but all children could walk within one year.ConclusionThe prognoses of childhood GBS, FS, and BBE were generally favorable, as long as the patient was promptly treated with either intravenous immunoglobulin or plasma exchange.     

Head titubation and irritability as early symptoms of Joubert syndrome with a homozygous NPHP1 variant

BackgroundJoubert syndrome is an autosomal recessive or X-linked genetic disease with a cerebellar vermis defect or hypoplasia, hypotonia, ocular dyskinesia, and mental retardation. In neonates, respiratory problems such as apnea and tachypnea are notable.Case reportWe report a patient Joubert syndrome with a homozygous NPHP1 variant, who had head titubation with irritability, including exaggerated jitteriness and a marked Morrow reflex appeared soon after birth without neonatal respiratory problems. These symptoms decreased gradually and disappeared until 1 year.ConclusionIrritability with head titubation may be an early clinical clue for the clinician to suspect Joubert syndrome.     

Clinical and molecular characteristics of tectonic (TCTN1) gene-related Joubert syndrome in a Saudi boy

Joubert syndrome (OMIM:609863) is a hereditary disorder characterized by hypotonia, developmental delay, and a distinctive cerebellar and brain stem malformation known as the molar tooth sign. Variants in tectonic genes TCTN1-3 have been described in a few patients with Joubert syndrome. Furthermore, Joubert syndrome attributed to variants in the TCTN1 (NM_001082538.2) gene has been only described in two reports. This report expands the clinical variability and molecular characterization of an emerging novel causative gene for Joubert syndrome in a Saudi boy born to non-consanguineous marriage with a c.1418del p.(Pro473Leufs*42) and c.800A > G p.(Tyr267Cys) representing a novel compound heterozygous variant of the TCTN1 gene identified by whole-exome sequencing and confirmed by Sanger sequencing. This is the first report of compound heterozygous Joubert syndrome type 13 from Saudi Arabia.     

A nation-wide survey of Japanese pediatric MOG antibody-associated diseases

ObjectiveTo elucidate the clinical characteristics of Japanese pediatric patients with acquired demyelinating diseases (ADS), positive for myelin oligodendrocyte glycoprotein antibody (MOG-IgG), we conducted a nation-wide survey.MethodsInformation about pediatric patients under 18 years old with ADS was solicited with surveys sent to 323 facilities. In an initial survey, we asked whether the center had any patients with ADS, and the MOG-IgG serostatus of the patients. In a follow-up survey, we requested more precise information on patients with ADS.ResultsInitial survey: 263 replies providing information on 175 patients were received. MOG-IgG were examined in 78 patients and 54 of those (69%) were positive for MOG-IgG. Follow-up survey: The characteristic involvement was optic neuritis, with visual disturbance and optic pain as characteristic symptoms. The relapse rate was 44% in patients positive for MOG-IgG, which was higher than that in seronegative patients (38%). For acute phase treatments, corticosteroid (CS), plasma exchange, and intravenous immunoglobulin (IVIG) were useful. To prevent relapse, CS, intermittent IVIG, immunosuppressants, and monoclonal antibodies were useful, but the efficacies of disease modifying drugs were uncertain. Sequelae such as visual disturbance, cognitive impairment, motor dysfunction, and epilepsy were observed in 11% of patients with MOG-IgG.ConclusionsMOG antibody-associated diseases were found to be common among pediatric ADS patients. Since a variety of sequelae were observed in these patients, it is important to identify the appropriate treatment to ensure the best outcome. The presence of the MOG autoantibody should be taken into consideration as part of the diagnostic criteria for pediatric ADS.     

Tourette syndrome in Japan: A nationwide questionnaire survey of psychiatrists and pediatricians

In order to shed light on the clinical picture of patients with Tourette syndrome (TS) treated at medical institutions in Japan, a nationwide survey covering both pediatric patients and psychiatric patients was conducted. We mailed 316 questionnaires on experience in treating TS cases and the patients' present conditions etc. to specialists such as psychiatrists and pediatricians. A total of 164 responded. The survey found 154 TS patients being treated at the time of survey, 45 (29.2%) had obsessive–compulsive symptoms (OCS), and 10 (6.5%) had family histories of TS. It was suggested that TS is often associated with OCS and that familial cases of TS are slightly less common in Japan than they are in the USA. Of the 116 respondents who described their experiences, 85 (73.2%) said that they had treated one or more patients displaying the symptoms of frequent coprolalia, and 42 (36.2%) said that they had treated one or more patients suffering from developmental disorders. Based on these findings, we speculated that the rate of coprolalia in Japan is a little higher than the previously reported 4% and that TS is often associated with developmental disorders.     

Joubert syndrome and related disorders

The cerebellum plays a role not only in motor control but also in motor learning and cognition. Joubert syndrome is a rare heterogeneous inherited genetic disorder characterized by ataxia, hypotonia, developmental delay, and at least one of the following features: neonatal respiratory disturbances or abnormal eye movement. The estimated frequency of Joubert syndrome in the United States is around 1 : 100 000. The term Joubert syndrome and related disorders (JSRD) has been recently coined to describe all disorders presenting with molar tooth sign on brain neuroimaging. Joubert syndrome is believed to be a representative of a new group of disorders named ciliopathies. The identification of seven causal genes (NPHP1, AHI1, CEP290, RPGRIP1L, TMEM67/MKS3, ARL13B, CC2D2A) has led to substantial progress in the understanding of the genetic basis of Joubert syndrome. The authors focus on clinical presentation of JSRD, differential diagnosis and molecular background.     

Compound heterozygous ADAMTS9 variants in Joubert syndrome-related disorders without renal manifestation

BackgroundCiliopathies are the outcomes of defects of primary cilia structures and functions which cause multisystemic developmental disorders, such as polycystic kidney disease, nephronophthisis, retinitis pigmentosa, Joubert syndrome (JS), and JS-related disorders (JSRD) with additional organ involvement including oral-facial-digital syndrome and so on. They often share common and unexpected phenotypic features.Case presentationWe report a 4-year-old-boy case with compound heterozygous variants of ADAMTS9. Unlike the cases with ADAMTS9 variants in the previous report, which identified that homozygous variants of ADAMTS9 were responsible for nephronophthisis-related ciliopathies in two cases, the current case did not have nephronophthisis nor renal dysfunction, and his clinical features, such as oculomotor apraxia, hypotonia, developmental delay, bifid tongue, and mild hypoplasia of cerebellar vermis indicated JSRD.ConclusionsThe case suggested a possible association between the clinical presentation of JSRD and ADAMTS9-related disease, and it shows a wide spectrum of ADAMTS9 phenotype.     

A controlled historical cohort study on the post-concussion syndrome

In Lithuania, expectation of chronic symptoms after minor head injury is less than in western countries and possibilities for monetary compensation are minimal. Therefore, an opportunity exists to study the post-concussion syndrome (PCS) without several confounding factors present in western societies. We sent questionnaires about symptoms attributed to PCS to 200 subjects who had a concussion with loss of consciousness between 35 and 22 months before the study. For each study subject, a sex- and age-matched control person with minor non-head injury was identified. These controls received similar questionnaires. All the responding post-concussion patients stated that they had had acute headache after the trauma but this headache had disappeared in 96% of cases within 1 month. Headache and dizziness at the time of the questioning were not significantly more prevalent in the patients with concussion than in the controls, and there was no significant difference concerning subjective cognitive dysfunction. Scores of visual analogue scales of symptoms attributed to PCS showed no significant differences except for depression, alcohol intolerance and worry about brain injury, which were more frequent in the concussion group. No specific effect of the head injury was detected when various definitions and different constellations of core symptoms of PCS were used. These findings question the validity of the PCS as a useful clinical entity.     

Meta-iodobenzylguanidine myocardial scintigraphy in Perry disease

IntroductionPerry disease (Perry syndrome), a hereditary TAR DNA-binding protein 43 (TDP-43) proteinopathy, is caused by dynactin subunit 1 (DCNT1) mutations and is characterized by rapidly progressive parkinsonism accompanied by depression, apathy, unexpected weight loss, and respiratory symptoms including central hypoventilation and central sleep apnea. Meta-iodobenzylguanidine (MIBG) myocardial scintigraphy is considered a diagnostic biomarker for Lewy body disease (LBD), as denervation of cardiac sympathetic nerves is a pathological feature in LBD. However, our previous studies have reported a decreased cardiac uptake of MIBG in patients with Perry disease. In this study, we aimed to correlate the MIBG myocardial scintigraphy findings with clinical features in Perry disease.MethodsWe evaluated data obtained from a multicenter survey of patients of Japanese origin with suspected Perry disease, who visited neurology departments in Japan from January 2010 to December 2018. We screened each patient's DNA for the DCTN1 mutation using Sanger sequencing and obtained the clinical details of all patients including findings from their MIBG myocardial scintigraphy.ResultsWe identified two novel mutations, p.G71V and p.K68E, in DCTN1 in patients from two different families. The majority of patients (7/8, 87.5%) showed a decrease in cardiac uptake (heart to mediastinum ratio) in MIBG myocardial scintigraphy. These patients commonly presented with symptoms related to autonomic dysfunction: constipation, fecal incontinence, urinary disturbance, and orthostatic hypotension.ConclusionsMIBG myocardial scintigraphy may be a useful biomarker of autonomic dysfunction in Perry disease.     

Inherited ADAMTS13 deficiency (Upshaw-Schulman syndrome): A short review

Congenital thrombotic thrombocytopenic purpura (TTP), also known as Upshaw-Schulman syndrome, is associated with an inherited deficiency of ADAMTS13, a von Willebrand factor-cleaving protease. It is a rare, life-threatening disorder characterized by thrombocytopenia, hemolytic anemia, neurological symptoms, renal dysfunction, and fever resulting from formation of platelet thrombi within the microvasculature. Patients have initial episodes mainly during infancy or early childhood, and are conventionally treated with fresh frozen plasma. However, a more appropriate approach based on recombinant ADAMTS13 is slated to begin shortly. Mutations throughout the ADAMTS13 have been identified in congenital TTP patients. The prevalence of this entity is probably underestimated because it is often not suspected, the clinical course is usually heterogeneous and most of the symptoms are common to other diseases. The present review summarizes our current knowledge about Upshaw-Schulman syndrome.     

Antiepileptic Drug Treatment of West Syndrome

Summary: We sent questionnaires about current therapy for West syndrome (WS) to 208 institutions at which the pediatric members of the Japan Epilepsy Society were in residence. One hundred twenty-nine institutions (62%) responded. Thirty-eight institutions (29.5%) treated symptomatic and cryptogenic WS differently. Vitamin B₆ was the most preferred first-line drug, followed by the combination of vitamin B₆ and valproate (VPA) or monotherapy with VPA. ACTH was the third choice among drugs. The combination therapy of vitamin B₆ and VPA was effective in 58.3% of the patients with symptomatic WS.     

Epileptic Seizures Induced by Animated Cartoon, "Pocket Monster"

Summary: Purpose: A large number of children had fits while watching the animated cartoon television (TV) program "Pocket Monster." To elucidate the seizures associated with the TV program, we administered a questionnaire survey in Aichi Prefecture, Japan.
Methods: The questionnaires were sent to 75 hospitals located in and around Aichi prefecture. The presence of epileptic seizures and the types of seizures were determined by three pediatric neurologists.
Results: Sixty-one hospitals responded to the questionnaire survey. Among 95 patients living in Aichi prefecture for whom enough information on seizure manifestations and EEG was available, ≤93 patients were considered to have epileptic seizures while watching the TV program. Most seizures occurred at a scene in which red and blue frames alternated at 12 Hz. Sixty-nine (74%) patients had no history of epilepsy. Thirty-nine patients had generalized seizures, and 49 patients had partial seizures. Partial seizures occurred more frequently in the younger age group than did generalized seizures. The EEG revealed a photoparoxysmal response (PPR) in 43% of patients. PPR was present not only in patients with a history of epilepsy (54%) but also in those with no history of epilepsy (38%).
Conclusions: Almost all seizures induced by the TV program "Pocket Monster" were epileptic, and partial seizures were induced more frequently than generalized seizures. The incidence of this "Pocket Monster"-induced seizures was roughly estimated as ≥1 in 4,923 individuals aged 6–18 years.     

Association between restless legs syndrome and depression in patients with chronic kidney disease

Restless legs syndrome (RLS) is reportedly associated with depression. This association may be mediated by both sleep-dependent and sleep-independent mechanisms. Here we analyze the association between RLS and depressive symptoms in patients with chronic kidney disease (CKD). We also assessed whether the relationship is independent of insomnia.In a cross-sectional study, socio-demographic parameters, laboratory data, and medical history were collected from 788 kidney transplant patients and 161 dialyzed patients. Insomnia, depression, and the presence of RLS symptoms were assessed with standard questionnaires. Patients with probable RLS had a higher prevalence of depressive symptoms than those without RLS (56% vs. 22% with vs. without RLS, respectively; P<.001). Patients presenting RLS symptoms had higher Athens Insomnia Scale (AIS) scores than patients without RLS [median AIS score (interquartile range): 7 (6) vs. 3 (4) with vs. without RLS, respectively; P<.001]. The AIS score correlated with the CES-D score (Spearman's rho=0.54, P<.001). In multivariate analysis, the presence of RLS symptoms was independently associated with depressive symptoms (OR=3.96, 95% CI 2.21-7.1, P<.001). This relationship remained significant even after including insomnia in the model (OR=2.9, CI 1.55-5.43, P<.001).The presence of RLS symptoms is associated with depression in patients with CKD. This relationship remained significant even after accounting for insomnia. Sleep-independent mechanisms may also contribute to the association between RLS and depression in patients with CKD.     

Joubert syndrome presenting with young-age onset ischemic stroke: a possible etiologic association

Joubert syndrome is a rare genetic disorder of childhood that is characterized by hypoplasia or agenesis of the cerebellar vermis in addition to brainstem malformations. Ataxia, hypotonia, developmental delay, and apnea-hyperpnea are the most prominent clinical symptoms of Joubert syndrome, but this condition can also affect multiple organs, making the clinical phenomenology of Joubert syndrome quite diverse. Seizures are the most common neurological complications of Joubert syndrome, but its neurological sequelae are poorly described because Joubert syndrome is very rare. Here we report an acute ischemic stroke in a 21-year-old woman with Joubert syndrome who had no conventional risk factors for early onset cerebrovascular disease. To date, this is the first report of an ischemic stroke in a patient with Joubert syndrome, and we believe this case may suggest an association between Joubert syndrome and extremely early onset cerebrovascular disease.     

Audit study of the new hospitalization for assessment scheme for forensic mental health in Japan

AIM: To clarify the components of hospitalization for assessment (HfA) and the management changes from the beginning of the scheme to the present.METHODS: This study is composed of two surveys. In 2013 survey, we created two paper questionnaires (facility and case questionnaires) for psychiatrists working in psychiatric hospitals accepting HfA patients. Questionnaires were sent to 205 hospitals that were identified as accepting the HfA cases, and responses were requested via mail. The facility questionnaire was designed to clarify the following specifications and characteristics of each facility: the facility organizer (public sector or private hospital), and the number of beds, psychiatrists, psychiatric nurses, occupational therapists, psychiatric social workers, psychotherapists, public health nurses, and patients treated through HfA during the survey period. The case questionnaire was then used to collect data of the patients under HfA based on the Medical Treatment and Supervision (MTS) Act who were discharged between July 1, 2012 and June 30, 2013. Gathered information included: legal information of each case, demographic data, past history of the offenders, issued offense and the relationship to the victim, information regarding past psychiatric testimonies, psychiatric diagnoses, contents of the treatment during HfA, information regarding seclusion and restraint during the HfA, the verdict of the District Court panel, and so forth. Next, we compared those results with relevant data obtained in 2007. The 2007 survey comprised data of HfA patients from July 15, 2005 (the date the MTS Act was enforced) to January 15, 2007.RESULTS: We obtained 171 cases, approximately a half of whole contemporary cases of HfA, from 134 facilities, of which 46 were national, prefectural, or semi-official hospitals, and 88 were private hospitals, in 2013 survey. The majority of subjects were male, schizophrenic, and experienced previous psychiatric treatment. The most frequent type of the offense was injury, followed by arson. Most of the subjects were medicated, and a few cases took psychotropic injection during the HfA. The frequency of injection was decreased in 2013 (χ² = 7.54, df = 1, P = 0.006) than in 2007. Psychiatric testimony was more likely to be conducted in 2013 (χ² = 8.56, df = 1, P = 0.004). The examiner psychiatrist was more likely to belong to the HfA facility to which the patient was hospitalized (χ² = 5.32, df = 1, P = 0.02). Hospitalization orders were more frequently selected in 2013 (χ² = 19.76, df = 3, P < 0.001), although the characteristics of the subjects had not changed.CONCLUSION: Although the management of HfA has improved in recent years, structural problems remain.     

Urinary, faecal and sexual dysfunction in patients with multiple sclerosis

The prevalence and nature of bladder and bowel dysfunction were examined in a population-based study of 221 patients with multiple sclerosis who returned postal questionnaires. This preliminary investigation was supplemented by personal review which also provided information on sexual dysfunction in 174 and laboratory and urodynamic tests in 152 participants. Thirty of 221 (14%) currently used an indwelling catheter, and 84 of the remainding190 (44%) reported symptoms of urinary dysfunction, of which the most common were urgency and frequency. Thirteen of 144 (9%) patients had biochemical evidence of renal dysfunction, and 40 of 132 (30%) had infected urine samples. Eleven of 54 patients in whom investigation of upper urinary tract was thought to be appropriate demonstrated abnormalities. Sixty-four of 221 (29%) patients had experienced faecal incontinence, and 120 of 221 (54%) were constipated. Fifty-six of 68 (82%) men and 55 of 106 (52%) women reported a deterioration in sexual activity, the commonest symptoms being erectile failure in men and fatigue in women. Received: 21 August 1998 Received in revised form: 27 April 1999 Accepted: 16 June 1999     

Risk of stroke in imaging-proven subclavian steal syndrome

To determine the risk of stroke in patients with subclavian steal syndrome (SSS). We identified 165 patients with imaging-proven SSS from two hospitals. Demographic, clinical and imaging data were retrospectively collected. Patients were followed up for stroke events. Stroke occurred in 43 patients with a median follow-up of 28 months. Seven of these cases were identified prospectively and 36 cases retrospectively. On multivariate analysis, presence of symptoms at presentation (p = 0.029) was a significant predictor of stroke. Presence of symptoms at presentation predicted stroke in imaging-proven SSS.     

MRI findings of optic pathway involvement in Miller Fisher syndrome in 3 pediatric patients and a review of the literature

Background: Miller Fisher syndrome (MFS) is a rare demyelinating condition which may have involvement of cranial nerves. There are a few case reports of optic pathway involvement in children. We describe 3 patients with optic pathway enhancement in pediatric patients with MFS. Case series: We retrospectively reviewed brain imaging findings in 17 pediatric patients with of Guillain–Barré syndrome (GBS) meeting Brighton criteria who had brain MRIs performed during their acute illness. Cranial nerve enhancement was seen in 6/17 patients and optic nerve/chiasm enhancement was seen in 3 patients. Conclusion: Cranial nerve enhancement and optic pathway in particular, can be seen in patients with MFS. Imaging findings do not always correlate with clinical manifestations of cranial nerve involvement.